PROJECT SUMMARY Cellular stress responses have evolved for the adaptation to ever-changing environmental conditions. Aging is accompanied by the cellular accumulation of non-functional biomolecules, including protein aggregates, and stress responses and cyto-protective mechanisms have emerged as important cellular mechanisms that prevent aging-related dysfunction and disease, including neurodegenerative disorders. Understanding how stress responses are regulated is therefore an important step towards developing new strategies for maintaining cellular homestasis and organismal health. While severe stress is detrimental for cells and organisms, a mild stress can be beneficial and improve health and lifespan, a biological phenomenon referred to as hormesis. This response is highly conserved amongst organisms and includes the induction of the heat-shock response. I recently reported that exposure of the nematode C. elegans to a mild hormetic heat stress also leads to the induction of autophagy, a homeostatic cellular recycling process that plays important roles in aging and age-related diseases. Consistently, I observed that autophagy genes are required for the long-term hormetic benefits on longevity. Importantly, I also discovered that a mild heat stress can improve multiple protein-folding disease models in an autophagy-dependent fashion. These findings highlight hormesis as a novel paradigm to protect against neurodegenetive diseases, and discovered autophagy to be an important cytoprotective mechanism in the beneficial response to heat stress in C. elegans. However, the regulatory mechanisms underlying autophagy induction in response to hormetic stressors are completely unknown. Importantly, my studies have indicated that hormesis-mediated induction of autophagy and proteostasis could be subject to transcriptional control. To understand the transcriptional mechanisms by which hormesis induces autophagy to improve proteostasis, I propose to use a strong combination of genetic screens and next generation seqeuencing in the tractable model organism C. elegans. I will discover novel regulators with effects on autophagy transcription and uncover the transcriptional changes important for the long-term hormetic adaptations that improve proteostasis. Understanding the regulatory mechanisms by which autophagy ensures cytoprotective effects in multi- cellular organisms like C. elegans will be important for the manipulation of autophagy in health as well as diseases with deregulated autophagy. These findings could thus have tremendous impact on how we treat protein-aggregation diseases.